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Дисертації з теми "Cassures simple-brin de l'ADN – Dissertation universitaire":
Chabot, Thomas. "Modulation de l'activité du Rad51 par le récepteur tyrosine kinase c-Met dans la réparation des cassures double-brin de l'ADN." Thesis, Nantes, 2020. http://archive.bu.univ-nantes.fr/pollux/show.action?id=360755d5-6a18-407f-9af7-fe215a83747f.
Genomic instability due to deregulation of DNA repair pathways may be at the onset of cancer and subsequently lead to resistance to chemotherapy and radiotherapy. Understanding these biological mechanisms is therefore essential in the fight against cancer. RAD51 is the core protein of the homologous recombinant double-stranded DNA repair pathway. This repair leads to faithful DNA repair. The recombinase activity of the RAD51 protein is finely regulated by post-translational modifications such as phosphorylation. Over the last decade, more and more studies have suggested the existence of a relationship between receptors with tyrosine kinase activity, which are often overactivated and involved in aggressiveness and cancer proliferation; and DNA repair. Among these receptors with tyrosine kinase activity, the c-Met/HGF-SF duo is often mutated, over-expressed or constitutively activated in many cancers and its inhibition has been shown to induce a decrease in repair by homologous recombination. Through this thesis, we show for the first time that c-Met is able to phosphorylate the RAD51 protein on four tyrosine residues located mainly in the human recombinase nucleofilament monomer- monomer interface. We show the implication of these phosphorylations on the activity of RAD51 in the different steps of homologous recombination. All the results obtained suggest the possible role of these modifications in the regulation of RAD51 and underline the importance of c-Met in the response to DNA damage
Laroussi, Haifa. "Étude des mécanismes moléculaires d'initiation du transfert conjugatif d'ICESt3, médiée par une relaxase MOBT chez la bactérie Gram+ Streptococcus thermophilus." Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0176.
Bacterial genomes evolve mainly through horizontal gene transfer. Bacterial conjugation is one of the major mechanisms for these transfers. Conjugation is mediated by integrative and conjugative elements (ICE). In addition to their transfer function, ICEs encode other functions that may provide an adaptive advantage to their host, such as resistance to antibiotics whose dissemination is a major public health issue. It is therefore necessary to understand how ICEs are transferred in order to limit their dissemination.The transfer of an ICE from a donor cell to a recipient cell requires its excision from the chromosome, its transfer from one cell to the other and then its integration into the genomes of the two partner cells. According to the literature, the initiation of ICE transfer is mediated by a nucleoprotein complex called relaxosome, whose key protein is the relaxase, a transesterase encoded by the element. The role of the relaxase is to perform a single-stranded cleavage on the DNA of the ICE at a conserved site, called nic. This cleavage releases a free 3'OH end, used as a primer to initiate rolling circle replication. The DNA-relaxase complex is then driven to the conjugation pore.During my PhD thesis, I studied ICESt3 from Streptococcus thermophilus which belongs to the ICESt3/Tn916/ICEBs1 superfamily, widespread among Firmicutes. These ICEs encode a non-canonical relaxase belonging to the MOBT family, which is related to the rolling circle replication initiators of the Rep_trans family. The general objective of my thesis was to elucidate the function of the RelSt3 relaxase in order to decipher the molecular mechanisms of initiation of conjugative transfer mediated by a MOBT relaxase.My work led to the identification of the RelSt3 binding site on ICESt3 origin of transfer (oriT). This site, called bind, is peculiar in that it is distant from the nic site, which is not the case for other relaxase families. RelSt3 possesses an HTH domain at its N-terminus. I have shown that this domain is required for the binding of RelSt3 to its bind site, and that it is important for its catalytic activity. Conjugation assays demonstrated that this HTH domain is crucial for the conjugative transfer of ICESt3. Structural predictions of the HTH domain in complex with DNA led to the identification of the interaction interface with the bind site, confirmed by mutagenesis. I also demonstrated that RelSt3 exhibits a nicking-closing activity and that it covalently binds to the 5' end of the cleaved strand, demonstrating that this enzyme participates in both initial and final steps of conjugation.In the literature, it has been shown that relaxases interact frequently with other accessory proteins, encoded by the ICE or by the host bacteria, participating in relaxosome formation. The second objective of my thesis was to identify RelSt3 partners. Comparisons with available data on ICEBs1 from Bacillus subtilis allowed to identify two candidate proteins, OrfL and OrfM, that may belong to the relaxosome of ICESt3, as well as a cellular helicase, PcrA , probably involved in the rolling circle replication. A characterization of these proteins was performed using biochemical and biophysical approaches. The interaction network between all of these proteins was established using in vitro approaches, as well as with the in vivo two-hybrid approach. These data provide a first insight into the components of the ICESt3 relaxasome. I also showed that OrfL and OrfM stimulate the catalytic activity of RelSt3 in vitro, and that they are both essential for ICESt3 conjugation.This work lead to a better understanding of the molecular mechanisms required during the conjugation of an ICE driven by a MOBT family relaxase
Saidj, Rachid. "Les gènes BRCA et FANC : implication dans la réparation des cassures double brin de l'ADN chez l'homme." Paris 5, 2006. http://www.theses.fr/2006PA05P609.
The BRCA and FANC genes (respectively implicated in breast cancer predisposition and in Fanconi anemia) are classified as “caretakers” tumor suppressor genes and are involved in the maintenance of genomic stability. These genes are tightly associated and could participate in a common pathway. The aim of my thesis work was to improve our understanding of there function in the DNA double strand break (DSB) repair in Human cells. By using molecular approaches based on intra- or extra- chromosomal substrates, carrying model-DSB, we studied the impact of siRNA mediated depletion of these factors on the two major DSB repair pathways in mammalian cells: End-joining (EJ) and Homologous Recombination (HR). We have shown that: (i) BRCA1 depletion severely impairs the EJ pathway, (ii) the novel interaction between BRCA1 and XRCC4 (a key actor of EJ), constitutes a molecular and functional link between BRCA1 and this repair pathway; (iii) depletion of the Fanconi genes products FANCF and FANCG, which belong to the core complex, leads to an impairment of EJ but does not affect HR; (iv) FANCJ and FANCD1/BRCA2 which act downstream of the complex, control HR. On conclusion, our work shows that the BRCA/FANC pathway is implicated in DSB repair, and suggests a tight specialisation of each gene
Jacquemont, Céline. "Rôle des gènes BRCA et FANC dans la réponse cellulaire aux cassures double brin de l'ADN." Paris 5, 2004. http://www.theses.fr/2004PA05N01S.
The aim of my thesis work was to better understand the role of BRCA and FANC genes, respectively implicated in familial breast and ovarian cancers and in Fanconi anemia (predisposing to leukaemia), in cellular response to DNA double strand breaks (DSB). The cell cycle progression in the presence of DSB and the recruitment of poteins involved in the processing of these lesions were studied. We demonstrated that a single mutated BRCA1 allele is sufficient to abrogate the intra S-phase checkpoint in the presence of DSB, and to impair the recruitment at sites of lesions of key proteins involved in DNA damage response. The severe reduction of the overall BRCA1 protein level observed in ionizing radiation-treated BRCA1 heterozygogous cells may be at origin of the observed defects. In contrast, in BRCA2 +/- and BRCA2 -/-/ FANCD1cells, the arrest of cell cycle progression is fully efficient in response to DSB
Nassour, Joe. "Rôle du stress oxydant et des cassures de l’ADN dans l’émergence néoplasique post-sénescence." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S022/document.
Senescence is a permanent cell-cycle arrest activated in response to DNA damage. If a cell escapes from this state, it should inherit mutations and could potentially initiate a tumor. NHDFs (Normal Human Dermal Fibroblasts) display a classical irreversible and stable senescence plateau. In contrast, senescent NHEKs (Normal Human Epidermal Keratinocytes) experience two different outcomes. Most of them undergo autophagic cell death and about one on 10000 spontaneously resumes mitosis and generates clones of transformed, mutated and tumorigenic cells.I contributed in a first time to studying the role of macroautophagy in the cell death / post-senescence neoplastic emergence balance of senescent NHEKs. We have shown that macroautophagy plays antagonistic roles during senescence, inducing cell death or promoting neoplastic transformation, depending on its level of activation. Indeed, the progenitors of post-senescent emergent cells display oxidative stress and autophagic activity levels slightly lower than the average, what allows them to avoid autophagic cell death and to ensure the quality control indispensable for mitosis re-entry.Since oxidative stress is the motor of the post-senescence neoplastic emergence in NHEKs, I wondered next whether oxidative stress could operate through the generation of some mutagenic DNA damage. I took advantage of the comparison of senescent NHEKs to NHDFs. I have shown that unlike NHDFs, NHEKs do not suffer from significantly shortened telomeres, nor accumulate DSBs, do not activate a DDR (DNA Damage Response) pathway and in consequence do not significantly activate the p53/p21 pathway. Instead, they suffer from a decrease in PARP1 expression, which compromises the repair of SSBs generated by oxidative stress. In consequence, SSBR foci, precisely XRCC1 foci, become persistent. These persistent foci initiate a signalization, through p38MAPK, which leads to up-regulation of p16INK4A and to cell cycle arrest. Notably, the accumulation of unrepaired SSBs is sufficient for the post-senescence neoplastic emergence phenomenon, in addition, paradoxically to its involvement in the onset of senescence.In conclusion, senescence results from the persistence of a DNA damage signalization, but the exact nature of the damages could vary in different cell types depending on their repair capacities and could dictate completely different outcomes. Namely, persistent DSBs, including telomeric ones, dictate a permanent tumor-suppressor cell cycle arrest, whereas persistent SSBs are permissive to mutation and senescence evasion
Hoff, Grégory. "Réparation des cassures double-brin et variabilité chromosomique chez Streptomyces." Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0288/document.
Ionizing radiation, desiccation or exogenous secondary metabolites are all factors that can cause DNA damage in soil bacteria, especially by triggering double strand breaks (DSB), the most detrimental harm for the cell. In prokaryotes, evolution selected two main DSB repair pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ). HR is almost ubiquitous in bacteria and relies on an intact copy of the damaged DNA molecule as a template for DSB repair. In contrast to HR, NHEJ is only present in 20 to 25% of bacteria and is considered as a mutagenic pathway since DSB repair is performed without the need of any template and can lead to nucleotide addition or deletion at DSB site. In the bacterial model Mycobacterium, two partners are sufficient for a functional NHEJ pathway. Thus, Ku protein dimer recognizes and binds the DSB and then recruits the multifunctional LigD protein for extremities treatment and ligation thanks to its polymerase, nuclease and ligase domains. At the beginning of this work, few informations on DSB repair in Streptomyces were available. This bacteria exhibits remarkable genomic features including a large linear chromosome (6 to 12 Mb). Regarding HR, we focused on the late stage (post-synaptic step) in studying the role of RuvABC complex and RecG, involved in branch migration and Holliday junction resolution in E. coli. Construction of single and multiple mutants showed that although the genes encoding these proteins are highly conserved in Streptomyces, their deficiency in Streptomyces ambofaciens only results in a mild decrease of recombination after conjugation events. Besides, no decrease of intrachromosomal recombination efficiency could be observed. These results suggest that major alternative factors are still to be discovered in Streptomyces. This work was also the first occasion to decipher a NHEJ pathway in Streptomyces. An exhaustive genomic study revealed a great diversity in the number of factors potentially implicated in this pathway (Ku, LigDom, PolDom, NucDom) and in the organization of their encoding genes. Functional analyses revealed that all the factors, whatever they are conserved or not between species, were involved in the response to electron beam exposure, known to induce, amongst other things, DSB formation. Generation of DSB by I-SceI endonuclease cleavage was also used to evidence at a molecular level NHEJ type DSB repair (deletions or insertions of several nucleotides, integration of DNA fragments). Targeted breaks in the terminal regions of the chromosome were accompanied by large deletions (up to 2.1 Mb) and major rearrangements including chromosome circularizations and DNA amplifications. Consequences of DSB repair in S. ambofaciens are in all points similar to chromosome rearrangements observed spontaneously or by comparing genomes of different species. Thus, it is possible to link the genome plasticity to DSB repair. In addition, the integration of exogenous genetic material would be favoured during NHEJ repair which would give this repair system a major role in the horizontal transfer process, known to be a main evolution mechanism in bacteria
Tsouroula, Aikaterini. "Double strand break repair within constitutive heterochromatin." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ036/document.
Heterochromatin is the tightly packed form of repetitive DNA, essential for cell viability. Its highly compacted and repetitive nature renders DSB repair a challenging process that cells need to overcome in order to maintain their genome integrity. Developing a highly specific and robust CRISPR/Cas9 system to target pericentric heterochromatin, we showed that DSBs in G1 are positionally stable and repaired by NHEJ. In S/G2, they relocate to the periphery of this domain to be repaired by HR. This relocation process is dependent of resection and RAD51 exclusion from the core domain of heterochromatin. If these breaks fail to relocate, they are repaired within heterochromatin by NHEJ or SSA. On the other hand, DSBs in centromeric heterochromatin activate both NHEJ and HR throughout the cell cycle. Our results reveal the differential repair pathway choice between centromeric and pericentric heterochromatin that also regulates the DSB position
Beck, Carole. "Caractérisation moléculaire et cellulaire du rôle de la poly(ADP-ribose) polymérase 3 (PARP3) dans la maintenance de l'intégrité du génome." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ075.
Poly(ADP-ribosyl)ation is a post-translational modification of proteins catalyzed by poly(ADPribose) polymerases (PARPs). PARP3 was identified as a novel actor of the double-strand break (DSBs) repair pathway. We evaluated the contribution of PARP3 in these repair pathways(HR, C-NHEJ ou A-EJ). Our results defined PARP3 as a modulator of the single strand DNA resection process which plays a role in driving the repair pathway choice. We showed that PARP3 enhances the recruitement of the Ku70/Ku80 complexe to damaged sites and modulates the BRCA1/53BP1 balance. These two events prevent the DNA end resection step initiating HR and A-EJ and drives the repair towards the C-NHEJ. By chromatin immunoprecipitation, we studied the consequences of the absence of PARP3 on histone modifications, known to modulate the decision of the DSBs repair pathways. Our current results didn’t allow us to establish a link between PARP3 and histone modifications in response to DSBs. However, in absence of DNA damage and PARP3, we observed an accumulation of H3K36me2, a histone mark known to regulate transcriptionally active genes. In a second project, we studied the impact of the absence of PARP3 on cell viability and tumor progression in breast cancer cell lines mutated in BRCA1. By in vitro and in vivo approaches, we showed that the absence of PARP3 induces an important decrease in cell survival and proliferation, an increase in centrosomal amplification and a strong delay in tumor progression. The roles of PARP3 in both cellular response to DNA damage and mitotic progression introduce PARP3 as a possible promising therapeutic target in cancer therapy